Dopamine is a neurotransmitter found in various parts of the central nervous system. It is most prevalent in the substantia nigra (A9), the neostriatum, and the ventral tegmental area (A10). Dopamine binds to two general classes of receptors, termed D1- and D2-like receptors. These receptors are differentiated pharmacologically, biologically, physiologically, and in anatomical distribution. Furthermore, the D1-like receptor class consists of several subtypes, D1 and D5. Likewise, the D2-like receptor class also consists of several subtypes, D2, D3, and D4. All of the subtypes of dopamine receptors are coupling to and activate different G protein complexes. The D1-like receptors interact with the Gs complex to activate adenylyl cyclase, whereas the D2-like receptors interact with Gi to inhibit cAMP production.
The D3 receptor subtype is found only in the CNS. It is found in greater abundance in the limbic regions of the brain, such as the nucleus accumbens. These regions receive dopamine input from the ventral tegmental area and are known to be associated with cognitive, emotional, and endocrine functions. It is relatively absent in the nigrostriatal system, suggesting that the D3 receptor may more likely be involved in the etiology of psychotic diseases, instead of locomotor abnormalities.
Many clinically efficacious antipsychotic agents, such as eticlopride, haloperidol, and olanzapine, bind to the D3 receptor. However, most of these compounds also bind to the D2 receptor, in addition to a host of other receptors and ion channels. High affinity of ligands for the D2 receptor in the striatum is believed to be the cause of serious extrapyramidal side-effects that can result in termination of therapy. In addition, this also has made elucidating the role of D3 more difficult.
Dopamine plays a major role in addiction, depression and psychosis. Many of the concepts that apply to dopamine apply to other neurotransmitters as well. As a chemical messenger, dopamine is similar to adrenaline. Dopamine affects brain processes that control movement, emotional response, and ability to experience pleasure and pain. Regulation of dopamine plays a crucial role in our mental and physical health. Neurons containing the neurotransmitter dopamine are clustered in the midbrain in an area called the substantia nigra. In Parkinson's disease, the dopamine-transmitting neurons in this area die. As a result, the brains of people with Parkinson's disease contain almost no dopamine. To help relieve their symptoms, these patients are given L-DOPA, a drug that can be converted in the brain to dopamine.
Certain drugs are known as dopamine agonists. These drugs bind to dopamine receptors in place of dopamine and directly stimulate those receptors. Some dopamine agonists are currently used to treat Parkinson's disease. These drugs can stimulate dopamine receptors even in someone without dopamine-secreting neurons. In contrast to dopamine agonists, dopamine antagonists are drugs that bind but don't stimulate dopamine receptors. Antagonists can prevent or reverse the actions of dopamine by keeping dopamine from attaching to receptors.
Dopamine antagonists are traditionally used to treat schizophrenia and related mental disorders. A person with schizophrenia may have an overactive dopamine system. Dopamine antagonists can help regulate this system by “turning down” dopamine activity.
Cocaine and other drugs of abuse can alter dopamine function. Such drugs may have very different actions. The specific action depends on which dopamine receptors the drugs stimulate or block, and how well they mimic dopamine. Drugs such as cocaine and amphetamine produce their effects by changing the flow of neurotransmitters. These drugs are defined as indirect acting because they depend on the activity of neurons. In contrast, some drugs bypass neurotransmitters altogether and act directly on receptors. Such drugs are direct acting.
Muscarinic acetylcholine receptors constitute a group of five receptor subtypes (M1–M5) that mediate cellular responses by activating heterotrimeric G proteins. These receptors are abundantly expressed throughout the central and peripheral nervous systems and play an important role in numerous physiological processes. Some of these include learning and memory, adjusting the amount of light that impinges on the retina, and regulating various organs innervated by autonomic nerves (e.g., gastrointestinal tract, heart, trachea and exocrine glands). In recent years, the signaling pathways of G protein-linked receptors have been worked out in great detail.
In the late 1980s, molecular cloning techniques identified the aforementioned five subtypes of muscarinic receptors. Each receptor shares common features including specificity of binding for the agonists acetylcholine and carbamylcholine and the classical antagonists atropine and quinuclidinyl benzilate. Each receptor subtype couples to a second messenger system through an intervening G-protein. M1, M3 and M5 receptors stimulate phosphoinositide metabolism while M2 and M4 receptors inhibit adenylate cyclase. The tissue distribution differs for each subtype. M1 receptors are found in the forebrain, especially in the hippocampus and cerebral cortex. M2 receptors are found in the heart and brainstem while M3 receptors are found in smooth muscle, exocrine glands and the cerebral cortex. M4 receptors are found in the neostriatum and M5 receptor mRNA is found in the substantia nigra, suggesting that M5 receptors may regulate dopamine release at terminals within the striatum. The structural requirements for activation of each subtype remain to be elucidated.
Acetylcholine and carbamylcholine bind to muscarinic receptors. Muscarinic responses to these ligands may produce excitation or inhibition and involve second messenger systems, as opposed to the direct opening of an ion channel. Muscarinic receptors are G protein-coupled receptors and mediate their responses by activating a cascade of intracellular pathways. Muscarine is the prototypical muscarinic agonist and derives from the fly agaric mushroom Amanita muscaria. Like acetylcholine, muscarine contains a quaternary nitrogen important for action at the anionic site of the receptor (an aspartate residue in transmembrane domain III).
The muscarinic antagonists scopolamine and atropine are derived from natural sources. They are both alkaloids (natural, nitrogenous organic bases, usually containing tertiary amines) from the nightshade plant Atropa belladonna. The potent anticholinergics are used to control the secretion of saliva and gastric acid, slow gut motility, and prevent vomiting. They also have a limited therapeutic use for the treatment of Parkinson's disease. In large doses however, the muscarinic antagonists with tertiary amines have severe central effects, including hallucinations and memory disturbances. In recent years, the quaternary muscarinic antagonist ipratroprium has been used in the treatment of chronically obstructed pulmonary disorder as an adjunct to β2 agonist therapy. M3 muscarinic receptors mediate bronchoconstriction in the airways. Muscarinic antagonists such as ipratropium and the long-lasting tiotropium are effective bronchodilators. Centrally active muscarinic receptor agonists show promise for the treatment of Alzheimer's disease. The rationale for therapy involves replacement of acetylcholine, which is depleted in Alzheimer's patients as the basal forebrain neurons degenerate. Muscarinic receptor agonists also show promise for treatment of peptic ulcers, pulmonary obstruction disorders, asthma, and urinary incontinence. An ideal candidate for a drug would have several features including high CNS penetration, high efficacy and selectivity for forebrain receptors and a low incidence of side effects.
Serotonin (5-hydroxytryptamine, 5-HT) is widely distributed in animals and plants, occurring in vertebrates, fruits, nuts, and venoms. A number of congeners of serotonin are also found in nature and have been shown to possess a variety of peripheral and central nervous system activities. Serotonin may be obtained from a variety of dietary sources; however, endogenous 5-HT is synthesized in situ from tryptophan through the actions of the enzymes tryptophan hydroxylase and aromatic L-amino acid decarboxylase. Both dietary and endogenous 5-HT are rapidly metabolized and inactivated by monoamine oxidase and aldehyde dehydrogenase to the major metabolite, 5-hydroxyindoleacetic acid (5-HIAA).
Serotonin is implicated in the etiology or treatment of various disorders, particularly those of the central nervous system, including anxiety, depression, obsessive-compulsive disorder, schizophrenia, stroke, sexual dysfunction, obesity, pain, hypertension, vascular disorders, migraine, psychosis, cognitive impairment, and nausea. Recently, understanding of the role of 5-HT in these and other disorders has advanced rapidly due to increasing understanding of the physiological role of various serotonin receptor subtypes. Most of the 5-HT receptors are G-protein coupled receptors, except for 5-HT3, which is an ion channel.
The 5-HT6 receptor subtype appears to be localized exclusively in the central nervous system, with high mRNA expression in the striatum. Other regions of the brain that have expression include olfactory tubercle, amygdala, and cerebral cortex. The receptor is coupled to activation of adenylate cyclase.
The 5-HT6 receptor may be involved in neuropsychiatric disorders, such as schizophrenia, depression, anxiety, and cognitive impairment. Various experiments using antisense oligonucleotides directed at 5-HT6 receptor mRNA support this hypothesis. However, the functions of 5-HT6 receptor are not well understood at this time.
Several antipsychotic drugs such as clozapine have high affinity for the 5-HT6 receptor subtype. The relationship between clozapine's binding to 5-HT6 and its antipsychotic properties is not clear. Other agents, such as amitryptyline (antidepressant), amoxapine (antidepressant), chlorpromazine (antipsychotic), clothiapine (antipsychotic), loxapine (anxiolytic), olanzapine (antipsychotic), pergolide (antiparkinsons), and perphenazine also have high affinity for the 5-HT6 receptor subtype. However, many of these agents also bind with high affinity to a host of other receptors and ion channels. This often leads to various side-effects that can result in termination of therapy. In addition, this also has made elucidating the role of 5-HT6 more difficult. Recently, several 5-HT6 antagonists have been reported, such as SB-271046 (Routledge, C. et al Br. J. Pharmacology 2000, 130, 1606–1612), Ro 04-6790, Ro 63-0563 (Sleight, A. J. Br. J. Pharmacology 1998, 124, 556–562), and a series of indoles and indolines (U.S. Pat. No. 6,187,805).